The regulation of immune responses is critically dependent on the development of T-cell subsets which produce particular cytokine profiles and not others, e.g., Th1 versus Th2 cytokines, in response to antigenic stimuli. In addition, the outcome of infection with a variety of pathogens is determined by the cytokines produced by antigen specific CD4+ T-cells, and inappropriate production of Th2 cytokines can result in the dissemination of infection or in allergic disease, while inappropriate production of Th1 cytokines can result in autoimmune pathology. The long term objective of this project is to elucidate the mechanisms that govern the development, activation and function of CD4+ T-cells with restricted cytokine profiles in antigen specific responses. In the previous project period, it was demonstrated that the antigen presenting cell (APC) type, cytokines such as IL-12 and IL-10 produced by APC, and genetic factors expressed at the level of the APC play a major role in governing the cytokine profile which develops in the CD4+ T-cell. The goal of this application is to further elucidate how these key elements allow APC to direct the developing cytokine profile in CD4+ T-cells. Specifically, these studies will: 1. Examine how macrophages from distinct strains of mice differentially regulate IL-4 and IFN-gamma during antigen specific immune responses; 2. Determine how differences in B-cells from distinct strains of mice control the quantity of IL-4 and IFN-gamma produced in CD4+ T-cells; 3. Examine the molecular mechanisms by which B-cells induce IL-4 synthesis in CD4+ T-cells. Insights gained from the proposed studies regarding the precise mechanism(s) that regulate cytokine synthesis should highlight potential therapeutic approaches likely to optimize the development of the appropriate T-cell subset.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024571-13
Application #
6170061
Study Section
Immunobiology Study Section (IMB)
Program Officer
Hackett, Charles J
Project Start
1986-09-01
Project End
2001-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
13
Fiscal Year
2000
Total Cost
$319,240
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Oh, Jae-Won; Seroogy, Christine M; Meyer, Everett H et al. (2002) CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation. J Allergy Clin Immunol 110:460-8
Walter, D M; McIntire, J J; Berry, G et al. (2001) Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J Immunol 167:4668-75
Walter, D M; Wong, C P; DeKruyff, R H et al. (2001) Il-18 gene transfer by adenovirus prevents the development of and reverses established allergen-induced airway hyperreactivity. J Immunol 166:6392-8
Hansen, G; Yeung, V P; Berry, G et al. (2000) Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: role of CD8+ T cells and IL-18. J Immunol 164:223-30
Tsitoura, D C; Blumenthal, R L; Berry, G et al. (2000) Mechanisms preventing allergen-induced airways hyperreactivity: role of tolerance and immune deviation. J Allergy Clin Immunol 106:239-46
Hansen, G; McIntire, J J; Yeung, V P et al. (2000) CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation. J Clin Invest 105:61-70
Hansen, G; Berry, G; DeKruyff, R H et al. (1999) Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 103:175-83
DeKruyff, R H; Fang, Y; Umetsu, D T (1998) Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL-12 production. J Immunol 160:2231-7
Yeung, V P; Gieni, R S; Umetsu, D T et al. (1998) Heat-killed Listeria monocytogenes as an adjuvant converts established murine Th2-dominated immune responses into Th1-dominated responses. J Immunol 161:4146-52
Tang, L; Benjaponpitak, S; DeKruyff, R H et al. (1998) Reduced prevalence of allergic disease in patients with multiple sclerosis is associated with enhanced IL-12 production. J Allergy Clin Immunol 102:428-35

Showing the most recent 10 out of 30 publications